(Circulation. 1997;95:1745-1748.)
© 1997 American Heart Association, Inc.
Articles |
Electrophysiological Remodeling of the Heart Owing to Rate
the Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, and the Roudebush Veterans Administration Medical Center, Indianapolis, Ind.
Correspondence to Douglas P. Zipes, MD, Krannert Institute of Cardiology, 1111 W 10th St, Indianapolis, IN 46202-4800.
Key Words: Editorials • atrium • ventricles • arrhythmia • fibrillation
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Introduction |
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 Top Introduction Effects of Prolonged Tachycardia...Effect of Transient Tachycardia...Effect of Prolonged Tachycardia...Effect of Transient Tachycardia...Clinical ApplicationReferences |
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Although damage to the heart from inflammation and infarction are well-established stimuli that trigger major cardiac remodeling, it has been known since 1954 that a persistent supraventricular tachycardia also can alter cardiac structure and function.1 This clinical observation was exploited 8 years later when it was demonstrated that rapid stimulation of the normal heart could produce reversible congestive heart failure.2 Since then, rapid pacing has been used frequently to create an investigational animal model of heart failure.
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Effects of Prolonged Tachycardia on Ventricular Electrophysiology |
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TopIntroductionEffects of Prolonged Tachycardia...Effect of Transient Tachycardia...Effect of Prolonged Tachycardia...Effect of Transient Tachycardia...Clinical ApplicationReferences |
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The effects of prolonged pacing-induced tachycardia, in the range of 250 bpm for 3 or 4 weeks, has been studied in depth in several animal species and has been shown to cause extensive myocardial remodeling. Biventricular enlargement with reduced wall thickness and no increase in muscle mass, reduced cross-sectional myocyte area and increased length, disarray of myofibril alignment and cytoarchitecture, increases in contractile protein degradation, and destruction of the supporting myocardial collagen matrix represent some of the structural changes contributing to reduced ventricular function.3 Diminished responsiveness to ß-adrenoceptor stimulation caused by a reduction in ß-receptor density and a variety of alterations in the adrenergic signaling processes also occur.4 Replacement fibrosis, loss of cells, and reactive hypertrophy of the remaining cells have been noted recently.5 mRNA levels for specific cytoskeletal proteins increase, along with alterations in cytoskeletal architecture6 and abnormalities in phospholamban.7
In pigs subjected to 3 weeks of a tachycardia-induced cardiomyopathy, myocyte action potential showed reduced membrane resting potential, reduced amplitude and upstroke velocity, and prolonged duration at 90% repolarization. Peak L-type Ca2+ current density was reduced because of an absolute reduction in L-type Ca2+ current flow into the myocyte possibly caused by reduced open probability of the channel.8 However, in dogs that had rapid ventricular pacing for 3 to 4 weeks, action potential duration was prolonged at least in part because of downregulation of Ito. Basal L-type Ca2+ current and whole-cell Na+ current did not differ in cells from control and failing hearts.9 Species differences and the ionic heterogeneity in the ventricular myocardium may help explain the different results from these two studies.
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Effect of Transient Tachycardia on Ventricular Electrophysiology |
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TopIntroductionEffects of Prolonged Tachycardia...Effect of Transient Tachycardia...Effect of Prolonged Tachycardia...Effect of Transient Tachycardia...Clinical ApplicationReferences |
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Recently, it has been noted that a ventricular rate change, even of short duration, can alter cardiac electrophysiological properties, which in turn can influence the propensity for developing or sustaining a cardiac arrhythmia. In dogs, for example, the transient superimposition of a fast ventricular rate on a slow rate was found to lengthen the QT interval, the duration of the ventricular action potential, and refractoriness and facilitate the induction of torsade de pointes. Changes caused by only 1 hour of rapid pacing persisted for at least 3 hours10 and were still present in disaggregated cardiac myocytes isolated from hearts subjected to the pacing protocol.11 The duration and rate of the superimposed tachycardia, as well as the rate of the bradycardia before rapid pacing, modulated the degree of refractory period prolongation, which was not influenced by autonomic denervation. Verapamil reduced but did not entirely eliminate the increase in refractoriness but suggested that intracellular Ca2+ overload mediated, at least in part, the changes.11 It is known that an increase in stimulation frequency increases steady-state muscle inotropy, presumably as a result of voltage- and frequency-dependent potentiation of L-type Ca2+ current, which in turn augments calcium release from the sarcoplasmic reticulum stores during the action potential. Elevated intracellular Ca2+ can also activate phospholipase C, which in turn could activate membrane-bound protein kinase C, ultimately leading to phosphorylation of ion channels/ion pumps, which could also mediate changes in refractoriness. Because the refractory period changes lasted so long, alterations in the proteins that regulate the potassium and other channels appeared to be the most likely explanation.
There may be clinical correlates to these laboratory observations. For example, if the patient with atrial fibrillation experiences torsade de pointes because of the acquired long-QT syndrome when treated with a drug like quinidine, he or she usually does so at the return of sinus rhythm, presumably when the rate suddenly slows.12 A second example is the patient who develops torsade de pointes soon after the sudden initiation of complete AV block by radiofrequency catheter ablation.13
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Effect of Prolonged Tachycardia on Atrial Electrophysiology |
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TopIntroductionEffects of Prolonged Tachycardia...Effect of Transient Tachycardia...Effect of Prolonged Tachycardia...Effect of Transient Tachycardia...Clinical ApplicationReferences |
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Recent investigation has centered on how rate remodels the electrophysiological properties of the atrium. Prolonged atrial pacing in goats14 and dogs15 16 at rates sufficiently rapid to produce atrial fibrillation causes reversible electrophysiological remodeling of the atria that is characterized by shortening of atrial refractoriness and loss of the normal decrease in refractoriness with an increase in rate. In fact, the relationship between refractory period and rate can become reversed so that instead of lengthening at slow rates, the refractory period actually shortens.14 In addition, after termination of pacing-induced atrial fibrillation for 10 to 14 weeks, sinus node function is depressed, raising the likelihood that the sinus node also becomes remodeled by this process.16 Perhaps the bradycardia in the bradycardia tachycardia syndrome is due in part to sinus node remodeling from the tachycardia. Conduction has also been assessed in these models. No change in conduction velocity along Bachmann's bundle was found,14 while in others,16 17 P-wave duration and intra-atrial conduction time prolonged.
After prolonged pacing-induced atrial fibrillation, the previously normal atrium now maintains stable sustained atrial fibrillation.14 15 16 This may result, at least in part, because the abbreviated atrial refractory period leads to shortening of the wavelength of the reentrant wavelets responsible for atrial fibrillation (wavelength is the distance traveled by the depolarization wave front during the duration of its refractory period and equals conduction velocity times refractoriness). A long wavelength may not permit reentry to sustain, causing the fibrillation to terminate, and may be the mechanism by which some drugs abolish atrial fibrillation. A short wavelength would allow a greater number of wavelets to coexist in the atria at one time, making it less likely, according to Moe's multiple wavelet hypothesis, that they will all extinguish simultaneously. The critical number of wavelets to sustain atrial fibrillation in an isolated canine heart is estimated to be four to six.18 Intra-atrial conduction disturbances16 17 would contribute to the maintenance of the atrial fibrillation, as would dispersion of atrial refractoriness. However, the pacing-induced atrial fibrillation model does not appear to increase dispersion of refractoriness, at least when determined at the two atrial appendages and estimated at multiple sites from the median atrial fibrillation interval.14
Studies in humans support the concept of rate-induced remodeling in the atrium by showing that the duration of the atrial monophasic action potential after termination of atrial fibrillation is shortened and that the degree of shortening correlates with the inability to maintain sinus rhythm.19 20 21 The refractory period has also been shown to lose its normal rate adaptation.21
The ionic basis of atrial action potential shortening may be a decrease in Ito and ICa.22 In atrial cells from humans with chronic atrial fibrillation, reduction in outward K+ current density and downregulation of Kv1.5 have been shown.23
Prolonged pacing-induced atrial fibrillation also can provoke anatomic changes in the atria. Biatrial enlargement15 17 and increased mitochondrial size and number with disruption of the sarcoplasmic reticulum15 have been described. An increase in connexin43 has been found in one study, despite development of coexisting intra-atrial conduction delay.17 In another study,24 the expression pattern of connexin43 was unchanged, while connexin40 showed discontinuities between islands of cells but did not appear to affect conduction velocity. Cells also undergo major myolysis and hypertrophy.25
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Effect of Transient Tachycardia on Atrial Electrophysiology |
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TopIntroductionEffects of Prolonged Tachycardia...Effect of Transient Tachycardia...Effect of Prolonged Tachycardia...Effect of Transient Tachycardia...Clinical ApplicationReferences |
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Recently, it was shown that atrial refractoriness in humans decreased by
25 ms after as little as 7 or 8 minutes of pacing-induced atrial fibrillation and facilitated reinduction of atrial fibrillation. Refractoriness returned to control values after about the same time interval.26 In this issue of Circulation, Tieleman et al27 present results in conscious goats subjected to 24 hours of atrial pacing at a cycle length of 200 ms. They found that atrial refractoriness shortened most in the first 4 hours and did so more at slow than fast rates, thus eliminating the normal pattern of physiological rate adaptation. Verapamil blunted the reduction in atrial refractoriness and shortened the time for refractoriness to return to control values; ie, it reduced the time constants for remodeling. With verapamil, no further shortening of refractoriness occurred after 8 hours of rapid pacing, and rate adaptation was still present. Return of refractoriness took <6 hours in the verapamil-treated dogs, whereas it still had not returned to original values in the control dogs. The inducibility of atrial fibrillation correlated with the duration of pacing, but despite a significant reduction in electrical remodeling, verapamil minimally reduced the inducibility of atrial fibrillation.
More Questions Than Answers
Although the above studies have advanced our knowledge about rate-induced electrophysiological remodeling, they raise some very interesting questions. For example, of fundamental importance is the ionic mechanism responsible for the cardiac remodeling of refractoriness. Because of the known effects of rapid rates on intracellular calcium influx and the observation that verapamil blunted the refractory period changes,10 27 one can assume that the L-type calcium channel is probably important in mediating some of the observed changes. Initial studies in atrial cells have shown a decrease in Ito and ICa,22 along with downregulation of Kv1.5.23 In ventricular myocytes, a reduction in L-type Ca2+ current8 and Ito9 have been found. However, other ionic species may also be involved. It is important to stress that the duration and rate of rapid pacing, the animal species, and the particular cells sampled may affect the ionic changes. Further, it is possible that pacing-induced electrophysiological remodeling after just hours or a day or two may represent a "purer" electrophysiological response to the rate intervention than after pacing for 3 to 4 weeks. The latter time course introduces major structural alterations,3 4 5 6 7 15 17 24 25 making it difficult to separate primary from secondary electrophysiological responses.
It is also of interest that both transient rapid ventricular pacing superimposed on a ventricular bradycardia10 and prolonged tachycardia8 9 lengthened the ventricular action potential and refractoriness. However, both transient and prolonged rapid pacing in the atrium or atrial fibrillation shortened atrial action potential duration and refractoriness.14 15 16 17 19 20 21 22 23 26 27 These opposite responses may be caused by differences in the conditions of the experimental protocols and/or tissue type but certainly raise the possibility of different ionic mechanisms for the two chambers despite the fact that a reduction in Ito and L-type Ca2+ current has been shown for both cell types. Whether the refractory period lengthens or shortens naturally could affect the nature of the arrhythmia induced, torsade de pointes in the ventricle, and atrial fibrillation in the atrium.
Although prolongation of refractoriness appears important for initiation of torsade de pointes in the ventricle, just how important shortening of atrial refractoriness is for the development of sustained atrial fibrillation can be questioned. First, verapamil, which blunted the atrial remodeling, had no major impact on atrial fibrillation induction.27 Second, despite major shortening of refractoriness over short time periods in the animal27 and clinical26 studies, sustained atrial fibrillation did not develop. Indeed, prolonged periods of pacing-induced atrial fibrillation are required for this to occur.14 15 16 17 Furthermore, both acute28 and more chronic29 atrial dilation have been shown to prolong atrial refractoriness but still facilitate induction of atrial fibrillation. These observations suggest that other electrophysiological and perhaps structural changes are required for atrial fibrillation to sustain, including atrial dilation,15 17 28 29 changes in mitochondria15 or connexin4317 expression or connexin40 distribution,24 or cell size.25 Depression of sinus node function may be important,16 as may the development of conduction delay in the atrium.16 17 The fact that no change in conduction velocity over Bachmann's bundle has been found14 24 27 but prolongation of P-wave duration and intra-atrial conduction have been noted16 17 evokes the possibility that Bachmann's bundle is relatively impervious to the remodeling stimuli, although other parts of the atrium are not. This naturally raises the very important question of whether remodeling occurs nonuniformly, affecting the crista terminalis, atrial free walls, appendages, sinus node and Bachmann's bundle, or various ventricular cells differently. Exploration of this issue and a more thorough morphological investigation are needed.
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Clinical Application |
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TopIntroductionEffects of Prolonged Tachycardia...Effect of Transient Tachycardia...Effect of Prolonged Tachycardia...Effect of Transient Tachycardia...Clinical ApplicationReferences |
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The clinical application of information from these electrophysiological studies seems readily apparent. As Tieleman et al27 point out, reduction of the electrical remodeling process might prevent or diminish the negative effects of prolonged atrial fibrillation on the success rate of conversion and maintenance of sinus rhythm and the atrial systolic dysfunction after cardioversion. It also might open the way to the development of new drugs or other techniques that would affect the remodeling process directly or might be best suited to function in the remodeled milieu to help maintain sinus rhythm. Similar conclusions can be applied to electrophysiological remodeling in the ventricle and its impact on heart failure and ventricular arrhythmogenesis. Certainly, exploration of electrophysiological remodeling of the heart owing to rate opens an area of important research for the future.
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Acknowledgments |
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This study was supported in part by the Herman C. Krannert Fund and by grant HL-52323 from the NHLBI of the NIH.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editor or of the American Heart Association.
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References |
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TopIntroductionEffects of Prolonged Tachycardia...Effect of Transient Tachycardia...Effect of Prolonged Tachycardia...Effect of Transient Tachycardia...Clinical ApplicationReferences |
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